2022 ELN recommendations for the management of AML in adults

The AML Hub has previously covered the 2022 recommendations from the European LeukemiaNet (ELN) for the diagnosis of acute myeloid leukemia (AML). Here, we summarize the updated guidelines for the management of AML, from the same publication in Blood,¹ by Döhner et al. on behalf of the ELN. This article includes a revised response criteria and treatment recommendations.

Response criteria and outcome measures

Alongside the categories outlined in the 2017 version of the recommendations, complete remission (CR) with partial hematologic recovery (CRh) has been introduced as a treatment response option for patients who meet all CR criteria but only have partial recovery of both neutrophils and platelets (Table 1).

Table 1. Treatment response criteria in AML*

Furthermore:

• Refractory disease is defined as no CR, CR with incomplete hematologic recovery (CRi), or CRh at the response landmark.
• Relapsed disease is indicated by bone marrow (BM) blasts ≥5%, or the reappearance of blasts in the blood in ≥2 peripheral blood samples collected ≥1 week apart, or the development of extramedullary disease.
• Minimal residual disease (MRD) relapse can be defined by the conversion from MRD negativity to MRD positivity, or by an increase of MRD copy number ≥1 log₁₀ between any two positive samples in patients with no CR, CRi, or CRh at the response landmark with MRD detection at low-level.
• It is recommended to report early death, for example at 30 and 60 days, to enable recording of treatment-related mortality (TRM).
• Event-free survival (EFS) and relapse-free survival (RFS) can be used as alternative endpoints to overall survival (OS), and the definition has been broadened to include CRh, CRi, and MRD outcomes:
  • EFS_MRD is measured from Day 1 of randomization (or Day 1 of registration in non-randomized trials) to the date of failure to achieve CR, CRh or CRi by a defined landmark, hematologic relapse, MRD relapse, or death from any cause.
  • RFS_MRD is measured from the date of achievement of remission until the date of hematologic relapse, MRD relapse, or death from any cause
  • Cumulative incidence of relapse (CIR_MRD) is measured from the date of achievement of remission until the date of hematologic relapse, or MRD relapse. Patients who died without relapsing are counted as a competing cause of failure.
  • Cumulative incidence of death (CID_MRD) is measured from the date of achievement of remission to death without prior relapse; relapse is considered as a competing risk.
• Within clinical trials, patients not achieving a response by or dying before the pre-determined landmark should have the event recorded on Day 1; alive but unevaluable patients should be censored on Day 1.

Therapeutic options

• Genetic analysis results should be made available as soon as possible, preferably within 3–5 days.
• Time should be taken before starting therapy allowing patients to be stabilized, and the most appropriate best treatment to be identified.
• The same therapeutic principles should be applied regardless of whether a patient is eligible for intensive therapy or if it is deemed that non-intensive therapy is more suitable.
  • If a patient cannot tolerate an active intensive or non-intensive treatment option with the aim of control and/or eradication of disease, the purpose of therapy should be to optimize quality of life and decrease the incidence of cytopenia-related complications with supportive care measures and early involvement of palliative care services as appropriate.

Fit patients

• Anthracyclines and cytarabine remain the primary induction options for intensive chemotherapy, with the multiagent regimen of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) and mitoxantrone-based cytarabine regimens as alternatives. Midostaurin is recommended to be incorporated in treatment regimens for patients with FLT3-mutated AML.
• Consolidation therapy should include intermediate-dose cytarabine when possible. In patients who have achieved CR, MRD assessment is helpful to inform consolidation treatment choice.
• Patients in first CR/CRi following intensive induction chemotherapy who are not able to complete intensive curative therapy, including allogeneic hematopoietic stem cell transplantation (allo-HSCT), can receive oral azacitidine maintenance therapy.
• Patients treated with midostaurin during induction and as consolidation therapy may continue it as maintenance.

Unfit patients

• In the absence of criteria to determine whether a patient is ineligible for intensive chemotherapy, criteria used in clinical trials may be of use in routine practice.
• Venetoclax or decitabine plus azacitidine is the new standard of care for patients unfit for intensive chemotherapy.
• Venetoclax plus low-dose cytarabine is an alternative for patients who cannot receive a hypomethylating agent.
• Rapid screening for IDH1 mutation at diagnosis is recommended to identify patients suitable for treatment with ivosidenib.
• Due to high incidences of early responses found with hypomethylating agent (HMA) combinations, patients receiving HMA combination should be evaluated for early response during the first cycle (Days 14–21). Early assessment can also inform dose management, such as changing or delaying doses in the event of persistent cytopenias in a leukemia-free BM.

Management of adverse events

Patients should be monitored closely to manage adverse events, particularly to novel therapeutics. The ELN recommendations for the management of adverse effects of novel agents are displayed in Table 2.

Table 2. Management of selected adverse events for novel agents*

Relapsed/refractory AML

• Molecular re-evaluation is important at relapse in order to identify potential targets for targeted salvage therapies.
• Patients should be entered into clinical trials where possible.
• Allo-HSCT is recommended if cytoreduction is achieved; non-intensive options for disease control, such as hypomethylating agents, are recommended if allo-HSCT is not an option.

Allo-HSCT

• Cytogenetic and molecular genetic features of disease, response to initial treatment, and patient, donor, and transplant factors should be taken into account when determining the risks and benefits of allo-HSCT.
• Allo-HSCT should be considered if there is a relapse probability of >35–40% without it.
• Allo-HSCT is not recommended for patients with favorable-risk disease in first CR unless there is inadequate MRD clearance but is recommended for patients with intermediate-risk and high-risk disease, depending on MRD status. Patients >60 years should be carefully selected for allo-HSCT, taking into account any co-morbidities.

• Where possible, sibling donor or well-matched unrelated donors are the preferred option for adults with AML; the use of relatives with deleterious germline variants should be avoided.
• For patients relapsing post-allo-HSCT with FLT3-mutated AML, gilteritinib is the preferred treatment option.

Clinical trials

• Patients with AML should be enrolled in a suitable clinical trial whenever possible, with real-time rapid-biomarker screening available to enable enrollment into trials of defined subpopulations.
• To maximize future research, biobanking should be standard practice for all clinical trials.

Special situations

• Patients with hyperleukocytosis (white blood cell count >100 × 10⁹/L) and those receiving venetoclax should be observed for tumor lysis syndrome.
• Patients receiving treatment with isocitrate dehydrogenase inhibitors should be closely monitored for signs of differentiation syndrome.

Supportive care

• A vaccination strategy for influenza and COVID-19 is recommended for all patients with AML.
• Consider antifungal prophylaxis with posaconazole during remission induction therapy.
• If regular blood counts are not possible, platelet and hemoglobin thresholds necessitating transfusion should be increased.
• The assessment of bleeding risk should include platelet count, mucosal bleeding, infection, severe mucositis, and fever; these factors indicate a need for an increased platelet level transfusion threshold.
• It is recommended to aim for hemoglobin levels of >8 g/dL, with a platelet count of <10 × 10⁹/L suggesting platelet transfusions are required.

Conclusion

Recent improvements in technologies and therapies for the management and treatment of patients with AML, and the influence these advancements have had on the standard of care and clinical trials, have informed the 2022 ELN recommendations.